The increasing prevalence of obesity in most industrialized nations has contributed to significant health complications, such as heart disease and cancer. At the source of the problem is our inability to control food intake when presented with excess food. Animal models, including rodents, suffer from the same inability to control intake and will gain weight when exposed to rich food in excess. It is important to understand how reward and motivation circuits of the brain regulate food intake and the nature of the dysfunction that causes obesity. Food intake is influenced by signals that travel from the body to the brain and considerable progress has been made toward identifying molecules, such as the leptin hormone, that signal the brain to modulate food intake. Leptin is secreted from fat cells in the body and serves to communicate the state of peripheral fat stores to the brain. It is critical to define the complete brain circuits that respond to leptin via direct action on its receptor. While most current research has focused on leptin receptor function within the hypothalamus, we have demonstrated that leptin signals directly to dopamine neurons of the midbrain to reduce feeding behavior. Conversely, reduction in leptin receptor activity in dopamine neurons leads to increased food intake. These ventral tegmental area (VTA) dopamine neurons are known to be important modulators of motivated behavior and play a particularly important role in the development of drug addiction. In this proposal, biochemical and genomic techniques will be used to elucidate the mechanism of leptin receptor signaling in VTA neurons. In addition, the neural circuits and behavioral consequences of leptin signaling to the VTA will be explored. Characterization of leptin effects in the VTA will produce a better understanding of how leptin modulates neurons to result in changes in food intake and general motivated behavior. In addition, defining the molecular pathways downstream of leptin receptor signaling will also elucidate potential interactions with other critical signaling pathways within the dopamine neurons of the VTA. These studies will generate a more complete understanding of leptin action in the brain and will contribute to our overall understanding of brain circuits that control ingestive behavior. PUBLIC HEALTH RELEVANCE: The increasing prevalence of obesity in most industrialized nations has contributed to significant health complications, such as heart disease and cancer. This proposal seeks to understand the neural and molecular mechanisms by which our body, via hormonal signals, regulates our food intake and motivation to eat food. By defining these critical molecules and neural mechanisms, we increase our understanding of obesity and identify possibly targets for drug development.